543P - P16(INK4A) Gene Hypermethylation and Kras Mutation are Independent Predictors of FolFiri and Cetuximab Chemotherapy in Patients with Metastatic Colorectal Cancer (MCRC)

Abstract

ABSTRACT Background P16 (INK4a) inhibits cyclin dependent kinases (CDKs) and plays various roles in cancer and senescence. P16 aberrancy is frequently detected in various cancers and may contribute to multidrug resistance. Hypermethylation of CpG island of p16 occurs in a significant proportion in colorectal cancer (CRC) and also is one of the CpG island methylator phenotype (CIMP) markers. Patients and method We analyzed tumor samples from 49 patients with metastatic colorectal cancer (mCRC) who were treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) and cetuximab (1st line 22 pts, 2nd line 27 pts). Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. To analyze the relation between methylation status of CIMP markers including p16 and clinical outcome, logistic regression and Cox regression were performed. Result Hypermethylation of p16 gene was detected in 14 of 49 patients (28.6%) and was significantly associated with KRAS mutation (Fisher's exact, P = 0.01) and CIMP+ (Fisher's exact, P = 0.002). Patients with p16 unmethylated tumors had significant longer time to progression (TTP, median 9.0 vs 3.5 months; log-rank, P = 0.001) and overall survival (OS, median 44.9 vs 16.4 months; log-rank, P = 0.008) than those with p16 methylated tumors. KRAS mutation was also associated with shortened TTP (median 8.9 vs 4.4 months; HR = 3.1, P = 0.008) and OS (median 44.9 vs 16.1 months; HR = 5.2, P Conclusion Promoter CpG island hypermethylation of p16 was predictive of clinical outcome in mCRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation. Disclosure All authors have declared no conflicts of interest.